The estrogen hormone has a broad spectrum of effects on tissues in both females and males. Many of these biological effects are positive, including maintenance of bone density, cardiovascular protection, central nervous system (CNS) function and the protection of organ systems from the effects of aging. However, in addition to its positive effects, estrogen also is a potent growth factor in the breast and endometrium that increases the risk of cancer.
Until recently, it was assumed that estrogen binds to a single estrogen receptor (ER) in cells. However, a second estrogen receptor, ER beta (ERβ), has been identified and cloned, with the original ER being renamed ER alpha (ERα). Endocrinology 1998 139 4252-4263. ERβ and ERα share about a 50% identity in the ligand-binding domain and only 20% homology in their amino-terminal transactivation domain. The difference in the identity of the two ER subtypes accounts for the fact that small compounds may demonstrate a higher affinity to bind to one subtype over the other.
Further, ERβ and ERα are believed to have varied distributions and functions in different tissues. For example, in rats, ERβ is strongly expressed in brain, bone and vascular epithelium, but weakly expressed in uterus and breast, relative to ERα. Further, ERα knockout mice are sterile and exhibit little or no evidence of hormone responsiveness of reproductive tissues. In contrast, ERβ knockout mice are fertile and exhibit normal development and function of breast and uterine tissue. These observations suggest that selectively targeting ERβ over ERα could confer beneficial effects in several important diseases, such as Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis and cardiovascular diseases, without the liability of reproductive system side effects. Selective effects on ERβ expressing tissues over uterus and breast could be achieved by agents that selectively interact with ERβ over ERα.
Accordingly, it would be advantageous to develop a series of novel compounds, which selectively modulate ERβ receptors and may be employed to treat a variety of estrogen-dependent pathological conditions.